The Consensus guidelines by the British Society of Gastroenterology as published in GUT August 2014 on the diagnosis & management of celiac disease are summarized by Utah Gastroenterology. For detailed information, please review the excellent guideline paper.

A multidisciplinary panel from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult celiac disease (CD). These recommendations of the British Society of Gastroenterology examine the diagnosis and management of CD, the classification of CD, genetics and immunology, diagnostics, serology and endoscopy, follow-up, gluten-free diet, refractory CD and malignancies, quality of life, novel treatments, patient support, and screening for CD.

 

Background

• CD is an immune-mediated small intestinal enteropathy triggered by exposure to dietary gluten in genetically predisposed individuals. Although the prevalence varies considerably, a large-scale study from Finland, Italy, the UK and Germany found a prevalence of CD of around 1%, with a recent US study showing a prevalence of 0.71%.
• CD is more frequently diagnosed in women than in men with a ratio between 1.5 and 2. Traditionally patients with CD presented with malabsorption, diarrhea, steatorrhea, weight loss or failure to thrive (‘classical CD’), but the proportion of newly diagnosed patients with ‘non-classical CD and even asymptomatic CD have gained prominence.  Screening may be initiated because the individual has a CD-associated disorder or has symptoms and is a first-degree relative to a patient with CD.
• Newly diagnosed patients with CD can present with a wide range of symptoms, including:
  • anemia
  • vague abdominal symptoms (often similar to irritable bowel syndrome (IBS))
  • neuropathy
  • ataxia
  • depression
  • short stature
  • osteomalacia and osteoporosis
  • liver disease
  • adverse pregnancy outcomes
  • lymphoma

 

Genetics, Immunology and Trigger Factors

• Environmental factors are important in CD and ingestion of gluten is a prerequisite for the development of CD. Children breastfed at and beyond gluten introduction may be at lower risk of developing CD in childhood, although research is not consistent. Gastrointestinal infections, drugs, interferon α and surgery have also been implicated as trigger factors. A high prevalence (10%) among first-degree relatives of patients with CD and a greater concordance rate in monozygotic twins (∼75%) than in dizygotic twins indicates a strong genetic component. CD shows a very strong association with a particular HLA variant termed HLA-DQ2.5. Most patients are DR3, DQ2 positive. A smaller subset of patients with CD express a very similar DQ2.5 molecule encoded by a combination of DR5 and DR7 positive haplotypes. While the proportion of individuals with CD who are DQ2.5 positive varies in different geographical areas it is generally ≥90%. The majority of the remaining patients are HLA-DQ8 positive (DR4, DQ8 haplotype).

 

Diagnosis of CD

• Diagnosis of CD is made by serology and duodenal biopsy, ideally with the patient on a normal gluten-containing diet.
• Biopsy remains essential for the diagnosis of adult CD and cannot be replaced by serology. Exceptions are patients with coagulation disorders and pregnant women, in whom biopsy may not be feasible or should be postponed until postpartum.
• The diagnosis of CD may not be straightforward, if patients are already on a GFD at the time of presentation, biopsies were not oriented correctly or show solely intraepithelial lymphocytosis (lymphocytic duodenosis) without architectural changes. In these situations, patients need to be maintained on a gluten-containing diet and additional testing or referral to a clinician with a specific interest in CD may be necessary.
• To state a definite diagnosis of CD, villous atrophy is required. However, lesser degrees of damage (≥25 intraepithelial lymphocytes (IELs) but no villous atrophy) combined with positive serology (IgA-endomysium antigen (EMA), tissue transglutaminase (TTG) or IgG-deamidated gliadin peptide (DGP) may also represent CD (‘probable CD’), and in these circumstances a trial with a gluten free diet (GFD) may be considered to further support the diagnosis of CD. Human leucocyte antigen (HLA) status may also aid diagnosis. Differential diagnoses of lymphocytic duodenosis should be ruled out if there is no response to GFD.
• The diagnosis of CD is readily established in those who have positive serology and a duodenal biopsy with obvious celiac histology (increased intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy) while consuming a gluten-containing diet. These patients can immediately initiate a GFD with confidence.

1. Serology in CD Diagnosis

• Serological detection depends on the presence of specific endomysial antibodies (EMAs), IgA anti-tissue transglutaminase antibodies (IgA-TG2, also called a-TTG, TTA) and/or deamidated antigliadin antibodies (DGP, either IgA or IgG isotype).7 IgG-TG2 is primarily useful in patients with known IgA deficiency.

2. Biopsy and Endoscopy in CD

• There are endoscopic markers of villous atrophy described – scalloping or reduction of duodenal folds and modularity – but these are not sensitive enough to preclude a biopsy, and a normal endoscopic appearance may occur in the presence of villous atrophy. Therefore, the endoscopic appearance of the duodenum should not determine whether biopsy is performed.
• Biopsy of the duodenum for a diagnosis of CD should be performed irrespective of the prior performance of serological tests, if the patient exhibits symptoms or signs of CD, such as diarrhea, weight loss or anaemia. Biopsies can be mounted on fibre-free paper to aid orientation, or alternatively biopsies could be free floated in formalin.
• The villous atrophy may be patchy in CD; hence multiple biopsies from the bulb and the more distal duodenum are recommended. The taking of at least four biopsy specimens is associated with a doubling of the diagnostic rate compared with patients undergoing a lower number of biopsies (less than four).
• In patients with persistently positive celiac serology but a normal mucosa, repeat small intestinal biopsy should be considered, including biopsies from the jejunum.
• Video capsule endoscopy may support a CD diagnosis in this setting.
• It is important that if serology has not been performed prior to the biopsy, then this must be carried out by the requesting physician on receipt of a histology report suggesting a diagnosis of CD. A biopsy finding of villous atrophy is not specific for CD. Although CD is the commonest cause of villous atrophy, there are other causes.
• Follow-up biopsies may be considered in patients with CD, and are potentially helpful in identifying patients at increased risk of lymphoma.
• Follow-up biopsies are not mandatory if the patient with CD is asymptomatic on a GFD, and has no other features that suggest an increased risk of complications.
• Follow-up biopsies should be undertaken in patients with CD whose condition does not respond to a GFD.

3. Histopathology Diagnosis of CD

The following features should be stated in the report:

1. Number of biopsies (including those from the duodenal bulb) and orientation.
2. The architectural features (normal, partial, sub-total or total villous atrophy).
3. Comment on the content of the lamina propria (in CD these are lymphocytes, plasma cells and eosinophils, and occasionally neutrophils, but cryptitis and crypt abscesses should suggest other pathology).
4. Presence of Brunner’s glands.
5. Presence of crypt hyperplasia, villous height: crypt depth ratio (3:1). The absence of plasma cells suggests common variable immunodeficiency.
6. Evaluation of IELs (with immunocytochemical staining for T cells (CD3) in equivocal cases) is vital. The normal count <25IELs/100 enterocytes should be taken as the norm.

4. Endoscopy in Seronegative Individuals

• The prevalence of seronegative CD is 6–22% of all diagnosed cases.
• Individuals of white European, Middle Eastern, North African or North Indian origin who undergo upper endoscopy for anemia, weight loss or diarrhea should have duodenal biopsies performed, irrespective of whether they have had serology for CD. These features may well indicate that CD or an alternative mucosal cause of malabsorption is present.
• It has been suggested that duodenal biopsy should be considered in any individual undergoing endoscopy, because CD is common and has many varied clinical manifestations, including reflux, a common indication for endoscopy.

5. Role of HLA in the Diagnosis of CD

• CD is associated with specific HLA types in virtually all populations and is associated with the carriage of the gene pairs that encode DQ2.5 and DQ8. The diagnostic value of HLA genotyping in patients who may have CD revolves around its high negative predictive value, meaning that patients who lack the appropriate HLA genotype pairs described above are very unlikely to have CD. However, the positive predictive value of the HLA genotyping for CD susceptibility is very low as a large proportion of individuals without CD carry either HLA-DQ2 or HLA-DQ8.
• HLA genotyping may be used in patients with suspected CD but who fail to respond to a GFD. A negative test in this circumstance would indicate that patients are highly unlikely to have CD (<1% of patients with CD are negative for DQ2 and DQ8) and thus the clinician can direct diagnostic efforts elsewhere.
• HLA typing may similarly be used in self-treated patients on a GFD (without prior appropriate testing for CD) before changing their diet. HLA typing may have an adjunctive role to identifying individuals who are not genetically at risk of CD and in whom further evaluation for CD is not necessary, saving a large number of repeated tests for CD in patients who would otherwise have to undergo testing because they have symptoms and a first-degree relative with CD.

6. Other Causes of Lymphocytic Duodenosis and Villous Atrophy

• Lymphocytic duodenosis is a common condition (3.8% of a population negative for coeliac serology) seen in association with infection (particularly Helicobacter pylori), altered immune states, for example, common variable immunodeficiency, autoimmune and chronic inflammatory disorders, drugs and neoplasia. There are other causes of villous atrophy in duodenal biopsies, including immune disorders and deficiency, food hypersensitivity, infection, drugs, neoplasia and miscellaneous disorders.

 

Dermatitis Herpetiformis (DH)

• Dermatitis herpetiformis (DH) is the cutaneous manifestation of gluten-sensitive enteropathy precipitated by exposure to dietary gluten. It is characterized clinically by herpetiform clusters of intensely itchy urticated papules and small blisters distributed on the extensor aspects of the elbows and knees and over the buttocks and on the scalp. The commonest age of onset is between the third and fourth decade. Male patients are affected twice as often as female patients. The major diagnostic criterion for diagnosis is the presence of granular IgA deposits in the dermal papillae of uninvolved perilesional skin as shown by direct immunofluorescence, and the diagnosis should not be made unless this has been confirmed. Less than 10% of patients with DH have symptoms or signs of malabsorption but most have evidence of CD that responds to a GFD and relapses on gluten challenge. Patients with DH present with skin manifestations and are not usually troubled by the underlying small bowel problem at the time of presentation. Abnormality of the small intestinal mucosa with either total or subtotal villous atrophy is found in approximately 70% of patients with DH. A further 25% have normal villous architecture with increased IELs. DH shares with CD an increased risk of developing lymphomas but this seems to be confined to those with severe gut involvement. The risk similarly declines with time on a strict GFD. Due to rash and itch, dapsone is often initiated. More than 70% of patients on a strict GFD are however able to slowly wean off dapsone over a period of 24 months.

 

Clinical Follow-up

• There is a paucity of data pertaining to adherence to a GFD being improved by follow-up in patients with CD. One of the key factors relating to adherence is dietetic input and regular follow-up. Patients should be encouraged to join disease-specific patient support groups. Once the disease is stable and the patients manage their diet without any problems, annual follow-ups should be initiated.
• The physician should check on small intestinal absorption
  • full blood count
  • ferritin
  • serum folate
  • vitamin B12
  • calcium
  • alkaline phosphatase),
• associated autoimmune conditions
  • thyroid-stimulating hormone and thyroid hormone(s)
  • serum glucose
• liver disease
  • aspartate aminotransferase/alanine aminotransferase
• dietary adherence
  • anti-TG2 or EMA/DGP
• In follow-up of CD, the key endpoints are normalisation of the health of patients judged by an absence of symptoms, and mucosal healing. Lack of symptoms or negative serological markers are not reliable or responsive surrogates of mucosal response to diet. The proportion of patients who do not achieve full histological recovery on diet varies, with most reports suggesting mucosal healing in 57–76%.
• Some experts favor repeat intestinal biopsy after 1 year of dietary therapy.

 

Assessing Adherence to the GFD, Gluten Challenge, and Medical Management during Follow-up

• Whilst the panel of experts agree adherence to the GFD is most important for the health of a patient with CD, there are no evidence-based recommendations regarding the most useful way to assess this. There are four steps to assess dietary adherence:
  • clinical assessment of symptoms
  • dietetic review
  • serum antibodies
  • follow-up biopsy
• Symptomatic patients should be evaluated more thoroughly than asymptomatic patients.
• To perform a gluten challenge, a 14-day gluten intake at ≥3 g of gluten/day (two slices of wheat bread per day) to induce histological and serological changes in the majority of adults with CD is recommended. The challenge can be prolonged to 8 weeks if serology remains negative at 2 weeks.
• Long-term medical follow-up can be in secondary care clinics or in primary care as long as the expertise is available. Prompt access to specialist or secondary care is recommended if any problems arise.
• The need for long-term follow-up is controversial.

 

Increased Risk of Osteoporosis and Bone Fracture

• It is recommended to measure calcium, alkaline phosphatase and vitamin D levels (and parathyroid hormone for compensatory increase) at diagnosis and replace as necessary.
• Calcium intake should be maintained at or above 1000 mg per day.
• Bone density should be measured in those at high risk of osteoporosis.
• Repeat bone density investigations (generally after an interval of ≥2 years) should be considered in patients who have low bone density on index measurement following initiation of appropriate treatment, or who have evidence of ongoing villous atrophy or poor dietary adherence.
• Postmenopausal women with CD may require supplementation in addition to the GFD.
• Loss of bone density at a greater than expected rate should prompt measurement of vitamin D levels, dietary review of adherence, consideration of repeat intestinal mucosal biopsy and review of additional risk factors such as hypogonadism.

 

Vaccination Recommendations 

• Hyposplenism associated with CD may result in impaired immunity to encapsulated bacteria. Hyposplenism does not seem to correlate with duration of GFD. Vaccination against Pneumococcus is therefore recommended. However, it is unclear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against Haemophilus,Meningococcus and Influenza should be considered if not previously given.
• It should also be noted that patients with CD may have a weaker response to hepatitis B vaccination than normal.

 

Screening for CD

• There is insufficient evidence to recommend population screening for CD, however there should be a low threshold for case finding in clinical practice as per National Institute for Health and Care Excellence guidelines. Symptomatic first-degree relatives of patients with CD should undergo CD testing.

 

Gluten-free Diet

• The mainstay of treatment of CD and DH is a GFD. The term gluten should be used to indicate not only wheat-based proteins (gliadins), but it also includes those from barley (hordeins) and rye (secalins), and cereal hybrids such as triticale. Research indicates that oats uncontaminated by gluten are probably safe for patients with CD. Patients with CD should be educated to avoid cereals and food containing gluten (breakfast cereals, flours, pasta, cakes, biscuits, sauces etc) derived from wheat, barley or rye and food made from gluten-contaminated oats, and encouraged to eat naturally occurring gluten-free foods and alternative sources of starch (corn, rice, potatoes etc).
• Patients must have a sufficient intake of nutrients, vitamins, fiber and calcium present in their GFD.
• Whilst contamination of the diet by gluten may be unavoidable a clinical response and mucosal recovery can be achieved by strict adherence to a gluten-free diet. Systematic study review suggests that while the amount of tolerable gluten varies among people with CD, a daily gluten intake of <10 mg is unlikely to cause significant histological abnormalities.
• Patients with CD complain about the limitations in their social life because of gluten-free meals or concern about the safety of food when eating out. The availability of gluten-free food is clearly limited in more rural areas and shopping for gluten-free food is time consuming. In most countries, high-quality gluten-free products are available in supermarkets or in special health food stores and on the internet, but the cost of gluten-free food is much greater than the equivalent wheat-based foods.

 

Patient Information and Support

• At diagnosis, patients should be encouraged to join their national celiac support group. In the UK, patients should be advised about gluten-free items on prescription (FP10), details of which are available from www.coeliac.org.uk. Further help can be found at several sites such as the Celiac Disease Foundation, www.celiac.com, or the National Foundation for Celiac Awareness.

 

Non-responsive CD (NRCD)

• After adoption of the GFD, 4–30% of patients with CD report persisting symptoms and are considered to be affected by non-responsive CD (NRCD). Inadvertent or deliberate gluten exposure is the most frequent cause of NRCD. Assessment for ongoing enteropathy plays a central role, therefore a follow-up biopsy is needed. Small bowel imaging should be performed in any patient with abdominal pain, persisting fever, obstruction, anaemia, gastrointestinal bleeding or unexplained weight loss. If duodenal biopsy does not reveal a persistent enteropathy, symptoms are likely to be due to a second condition. While the GFD is efficacious at controlling the signs and symptoms of CD and improving intestinal histology in most patients, virtually all individuals with CD will have symptomatic exacerbations due to gluten exposure and up to 30% of patients will have symptoms severe or chronic enough to visit their treating physician.
• NRCD may be considered in three categories.
  • First NRCD is due to continued dietary exposure to gluten.
  • Second, it may be due to a pre-existing or coincidental condition causing symptoms that resemble CD which may have led to the detection of otherwise asymptomatic CD.
  • Finally, it may be due to conditions associated with CD, such as secondary lactose intolerance, pancreatic exocrine insufficiency, small bowel bacterial overgrowth, microscopic colitis and cow’s milk protein sensitivity.

 

Refractory Celiac Disease (RCD)

• RCD is defined as persistent or recurrent malabsorptive symptoms and/or signs with villous atrophy despite a strict GFD for more than 12 months in the absence of other causes of villous atrophy or malignant complications and after confirmation of CD. In symptomatic patients with ongoing enteropathy and RCD, celiac-related malignancies and disorders that mimic CD must be excluded.
• RCD is subdivided into type I (RCDI) and type II (RCDII). The most important aspect of differentiating RCDI and RCDII is demonstration of a monoclonal population of T cells or aberrant T cells in the latter. Patients with RCDII have a poorer prognosis, due predominantly to nutritional complications and transformation into enteropathy-associated T-cell lymphoma (EATL). Ulcerative jejunoileitis (UJI) is a rare condition characterised by inflammatory ulceration of the small bowel that arises in RCD. The finding of UJI should raise suspicion for lymphoma.
• There is no standard treatment for RCD. Elemental diets, systemic steroids, oral budesonide, oral thioguanines including azathioprine are used in RCDI, but have limited benefit in RCDII. In RCDII, cyclosporine, cladribine and high-dose chemotherapy with autologous stem cell support have been reported; however, therapy must be individualised and include surveillance for EATL.
• EATL is a rare lymphoma strongly associated with RCDII, which carries a poor prognosis with a cumulative 5-year survival of less than 20%. Currently, two groups of EATL are recognised: EATL type I accounts for 80–90% of all cases and is a large cell lymphoma exclusively associated with CD. In contrast, EATL type II has not been associated with CD.
• The poor prognosis of EATL is determined by extent of disease at diagnosis, multifocal small bowel involvement, poor general health and presence of complications including perforation that preclude chemotherapy.
• Presence of RCDII is associated with a poor prognosis compared with isolated EATL in CD without RCDII.
• There is no proven effective treatment in RCDII, though a number of strategies have been proposed, and patients should be referred to a tertiary centre to optimise their management.
• Finally, numerous studies have confirmed the association between CD and B-cell lymphoma and small intestinal adenocarcinoma.

 

Novel Treatment

• None of the available novel treatments can as yet be recommended for use outside clinical trials.

 

In Summary 

• The treatment of CD is a lifelong and strict GFD. The goal of treatment is to relieve symptoms, achieve mucosal healing, avoid complications of CD. Follow-up of CD is needed to ensure response to symptoms, prevention of consequences, and continued maintenance of motivation to remain gluten free.
• Adequate (more than four) biopsies should be taken, from the distal duodenum and the duodenal bulb to maximise diagnosis.
• Duodenal biopsies are recommend  before the diagnosis of CD.
• Ideally a combination of serology and biopsies done on a gluten-containing diet will then provide the most robust diagnosis of CD.
• Specific serology such as IgA-TG2 and IgG-DGP with or without a strategy for determination of total IgA level should be the preferred serologic strategy for detection of CD.
• The paper recommends testing for CD in those with suggested symptoms or syndromes, especially if they have a first-degree relative with CD.

Recommendations

1. Diagnosis of CD requires duodenal biopsy when the patient is on a gluten-containing diet and for the vast majority of adult patients also positive serology.
2. Biopsy remains essential for the diagnosis of adult CD and cannot be replaced by serology. Follow-up should aim at strict adherence to a gluten-free diet.
3. In individuals undergoing an upper endoscopy in whom laboratory tests or symptoms or endoscopic features suggest CD, duodenal biopsy should be considered.
4. Duodenal biopsy should be retained as the mainstay for the diagnosis of adult CD and cannot be replaced by serology.
5. At endoscopy, if there is suspicion of CD, then at least four biopsy specimens should be obtained, including a duodenal bulb biopsy.
6. In serologically negative patients showing signs of malabsorption (such as anemia or diarrhea) or a family history of CD, a duodenal biopsy should be considered.
7. Follow-up biopsies may be considered in patients with CD, and are potentially helpful in identifying patients at increased risk of lymphoma.
8. Follow-up biopsies are not mandatory if the patient with CD is asymptomatic on a GFD, and has no other features that suggest an increased risk of complications.
9. Follow-up biopsies should be undertaken in patients with CD whose condition does not respond to a GFD.
10. HLA typing should be used to rule out CD. A positive DQ2.5 or DQ8 can never confirm the diagnosis.
11. HLA typing should be used in individuals who are self-treated on a GFD and never had appropriate testing for CD before changing their diet.
12. HLA typing can be used to rule out CD, and minimise future testing, in high-risk individuals with CD, for example, first-degree relatives.
13. When dietary adherence is questioned, it should be reviewed by a dietitian.
14. Symptomatic patients should be evaluated more thoroughly than asymptomatic patients.
15. Patients with CD require follow-up by a dietitian and/or clinician with an interest or expertise in this field.
16. Patients should have annual haematological and biochemical profiles.
17. Newly diagnosed patients should have vaccination for Pneumococcus.
18. Bone density should be measured after 1 year of diet in patients who have additional risk factors for osteoporosis or if over the age of 55 years.
19. Adult patients with CD should have a calcium intake of at least 1000 mg per day.
20. A GFD is the core management strategy for prevention of osteoporosis.
21. There is insufficient evidence to recommend population screening for CD, however there should be a low threshold for case finding in clinical practice as per National Institute for Health and Care Excellence guidelines.
22. Symptomatic first-degree relatives of patients with CD should undergo CD testing.
23. Patients should adhere to a GFD and have an intake of less than 10 mg gluten per day.
24. Gluten challenge is not recommended in the ordinary patient with CD, but in patients in whom the diagnosis remains unclear despite a follow-up biopsy, gluten challenge should be performed.
25. Patients may commence gluten-free oats at diagnosis.
26. A GFD is recommended to decrease the excess risk of adverse foetal outcome and of lymphoma among patients with CD.
27. At diagnosis, patients should be encouraged to join their national celiac support group.
28. Patients with persistent symptoms despite a GFD should have a follow-up biopsy.
29. In symptomatic patients with ongoing enteropathy and RCD, coeliac-related malignancies and disorders that mimic CD must be excluded.
30. Small bowel imaging should be performed in any patient with abdominal pain, fever, obstruction, anaemia, gastrointestinal bleeding or unexplained weight loss.
31. Patients with RCD should be referred to a tertiary centre to optimise their management.
32. None of the available novel treatments can as yet be recommended for use outside clinical trials.

 

http://gut.bmj.com/content/63/8/1210

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http://www.bsg.org.uk

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